tbuckley/cabot-search huggingface dataset:
Abstract 3985: TGF-B/KLF10 signaling regulates muscle wasting in pancreatic cancer cachexia
Authors: Daniel F. Gibbard, Aneesha Dasgupta, Rebecca E. Schmitt, Alexandra M. Ducharme, Paige C. Arneson, Elizabeth S. Bruinsma, John R. Hawse, Jason D. Doles
Journal: Cancer Research (2022)

Abstract Cancer cachexia, and its associated complications, represent a large and currently untreatable roadblock to better cancer therapy. Many potential therapies have been suggested and tested - including appetite stimulants, targeted cytokine blockers, and nutritional supplementation, but effective therapies have still not found a place in the clinic. Thus, a new approach to treating cancer cachexia is warranted. Members of the Kruppel-like factor family play wide-ranging and important roles in the development, maintenance, and metabolism of muscle. Upon review both our own and multiple publically available datasets, we identified KLF10 upregulation in a multitude of cachectic muscles - including in pancreatic, lung, and colon cancer mouse models and in human cachexia patients. Thus, in this study, we interrogated loss-of-function of KLF10 in the context of pancreatic cancer associated muscle wasting. Ex vivo experiments on satellite cells isolated from KLF10 Knockout (KO) mice showed resistance to the effect of KPC conditioned media on atrophy. In vivo studies using a KLF10 KO mouse model showed that upon orthotopic implantation of T4-KPC cells, the mice demonstrated a significant preservation of lean mass and significant alterations in the expression of muscle-specific ubiquitin ligases Trim63 and Fbxo32, as well as other genes implicated in atrophy, calcium signaling, and autophagy. Pathway analysis of RNA-seq data from these mice identified TGF-B, a known inducer of KLF10, as an important upstream regulator of the response. Further in vivo experimentation showed KLF10 KO mice to be resistant to the atrophic effects of TGF-B injections. In conclusion, we report a novel role of KLF10 in the manifestation of cachexia in pancreatic cancer. Citation Format: Daniel F. Gibbard, Aneesha Dasgupta, Rebecca E. Schmitt, Alexandra M. Ducharme, Paige C. Arneson, Elizabeth S. Bruinsma, John R. Hawse, Jason D. Doles. TGF-B/KLF10 signaling regulates muscle wasting in pancreatic cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3985.
Abstract 5134: Biomarker concordance between matched primary and metastatic colorectal tumors
Authors: Yun Yang, Ying Xin, Jianning Song, Chao Jing, Baoyi Zhao, Depei Huang, Wei Deng
Journal: Cancer Research (2022)

Abstract Background: Distant metastasis accounts for ~90% of deaths from colorectal cancer (CRC). The use of biomarkers for targeted therapy in metastatic CRC is well-established, requiring genetic testing of primary or metastatic biopsies. Here we aimed to assess the concordance of actionable alterations in matched primary and metastatic colorectal tumors. Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in a CAP/CLIA-approved laboratory (3DMed). NGS testing for SNV, InDel, CNV, MSI and TMB were performed on 19 primary tumors and 23 matched metastatic biopsies. Results: 42 matched primary and metastatic tumor samples from 19 CRC patients were analyzed. 68.4% of the patients had only liver metastases, 5.3% ovarian metastases, 5.3% peritoneal metastases and 10.5% of the patients had more than one metastatic site. Mutational landscape showed that the primary samples and the metastases shared 80% of top 20 mutations. Biomarker concordance for KRAS was 89.5% (17/19), NRAS was 89.5% (17/19), BRAF was 94.7% (18/19), EGFR was 89.5% (17/19), BRCA2 was 94.7% (18/19) and MS status was 100% (19/19). Inconsistent RAS/BRAF status was found in two liver metastases and one ovarian metastasis. The frequencies of SRC amplification (P = 0.08) and ACVR2A mutation (P = 0.31) seem to be higher in the primary tumors, although these were not statistically significant. Conversely, mutations of NRAS, EGFR and MAP2K4 were detected only in the metastases. One patient harbored EGFR amplification in the ovarian metastasis, while this variant was not present in liver and primary sites. Copy number loss of MAP2K4 was found in the metastatic biopsies of two patients. Tumor mutation burden was comparable between the primary tumors and metastases (3.12 vs 2.17muts/Mb, P=0.29). Conclusions: Our results demonstrates high concordance across multiple biomarkers between the primary and paired metastatic colorectal tumors. Molecular features of ovarian metastasis is more prone to inconsistent with primary sites than liver metastasis, which remains to be further verified in a large population. Citation Format: Yun Yang, Ying Xin, Jianning Song, Chao Jing, Baoyi Zhao, Depei Huang, Wei Deng. Biomarker concordance between matched primary and metastatic colorectal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5134.
Abstract 3658: Ototoxicity of chemotherapy and radiation agents used in pediatric cancer treatment
Authors: Brittney T. Moore, Fern Tsien, Gabrielle Sheets, Ayesha Umrigar, Jordan Doss, Michael Norman, Matthew Stark, Pinki Prasad, Amanda Musso, Chindo Hicks, David Otohinoyi, Jovanny Zabaleta, Li Li
Journal: Cancer Research (2022)

Abstract Many highly effective therapies used to treat cancer have been associated with irreversible development of detrimental neurological sequelae following the survival of childhood and adolescent cancer. While cancer treatment-induced late effects vary due to patient-related risk factors, cancer survivors who received chemotherapy or radiation may develop conductive or sensorineural hearing loss (SNHL). The purpose of this project is to determine which neuroinflammation-associated genes and biological pathways are affected by pediatric cancer treatments, and which treatment protocols are associated with increased ototoxicity. We hypothesize that cancer treatment causes abnormal gene expression of neuroinflammation and deafness-associated genes. The hypothesis will be tested with two specific aims. Aim I is to perform a retrospective review of diagnostic audiograms from pediatric cancer survivors enrolled in the Treatment After Cancer and Late Effects Center at Children’s Hospital New Orleans, Louisiana (CHNOLA). Aim II is to perform Nanostring neuroinflammation gene expression analysis followed by Ingenuity Pathway Analysis (IPA) of brain autopsy specimens from deceased pediatric patients who have previously undergone cancer treatment (Pathology Department, CHNOLA). Preliminary results revealed abnormal upregulation or downregulation of key genes, some of which are related to hearing loss and cochlear neuron degeneration when compared to age-matched controls (e.g., GJA1 and CASP3). The present study may provide information regarding which cancer treatment agents are ototoxic and reveal the candidate risk genes and pathways that contribute to auditory late effects. The long term goal of this project is to identify the needs of cancer survivors who are affected by treatment-induced hearing loss and provide them and their families with access to educational materials, medical resources, and social support to increase their health-related quality of life. Citation Format: Brittney T. Moore, Fern Tsien, Gabrielle Sheets, Ayesha Umrigar, Jordan Doss, Michael Norman, Matthew Stark, Pinki Prasad, Amanda Musso, Chindo Hicks, David Otohinoyi, Jovanny Zabaleta, Li Li. Ototoxicity of chemotherapy and radiation agents used in pediatric cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3658.
Addressing the big business of fake science
Authors: Robert M. Frederickson, Roland W. Herzog
Journal: Molecular Therapy (2022)

As noted previously in these pages, 1 Frederickson R.M. Herzog R.W. Keeping them honest: fighting fraud in academic publishing. Mol. Ther. 2021; 29: 889-890https://doi.org/10.1016/j.ymthe.2021.02.011 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar the scientific research community worldwide has been forced to reckon with the increasing problem of scientific fraud and the emergence of so-called "paper mill" industries 2 Else H. Van Noorden R. The fight against fake-paper factories that churn out sham science. Nature. 2021; 591: 516-519https://doi.org/10.1038/d41586-021-00733-5 Crossref PubMed Scopus (45) Google Scholar that manufacture fake scientific papers for a fee. The rapid proliferation of such services in the past decade or so, coupled with the pressures upon many young scientists around the globe to publish, has flooded many journals with papers that contain data that have been massaged to fit the narrative or, in some cases, have been completely invented. Unfortunately, this places a not insignificant extra burden on editors and reviewers, who now must take extra steps in an attempt to identify such papers up front so as to not waste the time of our limited editorial staff and volunteer editors and reviewers. At the Molecular Therapy family of journals, we now have many software tools at our disposal to detect these problems, and all authors of papers submitted to the journals are fully vetted to validate their laboratories of origin and author publication history. All images are carefully screened, and a plagiarism check is completed for every new submission. These procedures appear to be working, but of course, the worry remains that as we get better at detecting fraud, the perpetrators will only become better yet at producing it and may, in the future, be aided by artificial intelligence (AI) technologies.
Abstract 776: Expression of SOX15 and Wnt pathway genes in papillary thyroid carcinoma
Authors: Ayse Nur Buyru, Ayşegul Soysal, Ahmet Ozaydın, Betul Seyhan, Soykan Arıkan, Nejat Dalay
Journal: Cancer Research (2022)

Abstract Although thyroid cancer (TC) is a rare cancer with a rate of 2.1%, it is the most common cancer type among endocrine tumors. The molecular mechanisms of thyroid cancer, which develops as a result of environmental and genetic factors, are still unclear. SOX family genes are transcription factors that are expressed in a tissue-specific manner and play a role in the developmental processes. SRY-box transcription factor 15 (SOX15) is an important member of the SOX family and is involved in carcinogenesis. Its downregulation has been associated with the development and progression of different human malignancies. Some SOX family members have been reported to control cell proliferation by acting as negative regulators of the Wnt/β-catenin signaling pathway. MYC, CCND1 and CTNNB1 genes are important components of the Wnt signaling pathway. Recently, we have shown that epigenetic silencing of the SOX15 gene is associated with the pathogenesis of papillary thyroid carcinoma,In the present study, to further the understanding of the molecular mechanisms of SOX15 in papillary thyroid carcinoma (PTC) we investigated SOX15 expression in association with the transcriptional targets of the Wnt/β-catenin pathway.Primary thyroid tumors and adjacent nonmalignant tissue samples were collected from 52 patients, prior to any treatment. Total RNA was isolated from tissue samples and reverse transcription was performed. Expression levels of the SOX15, CTNNB1, c-MYC and CCND1 genes were analyzed by qRT-PCR using the SYBR green and Light-Cycler 480 system (Roche Diagnostics, Germany). β2M was used as the reference to normalize the mRNA levels. Statistical analysis was performed using the SPSS 21.0 (IBM® SPSS® Statistics, IBM Corporation Somers, NY, USA) program.SOX15 gene expression was significantly downregulated in 64.6% of PTC tissues compared to their normal counterparts. In contrast, CCND1, CTNNB1 and c-MYC gene expressions were significantly upregulated in 70.2%, 60% and 57.8% of the patients. Among the group of patients with downregulated SOX15 expression CCND1, CTNNB1 and c-MYC expression were upregulated in 46.8%, 40% and 40% of the subjects, respectively. Our data suggest that SOX15 downregulation may contribute to activation of Wnt signaling and provides further evidence indicating involvement of SOX15 in modulating the Wnt/β-catenin pathway in thyroid carcinogenesis. Citation Format: Ayse Nur Buyru, Ayşegul Soysal, Ahmet Ozaydın, Betul Seyhan, Soykan Arıkan, Nejat Dalay. Expression of SOX15 and Wnt pathway genes in papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 776.
Insights Into the Metabolic Aspects of Aortic Stenosis With the Use of Magnetic Resonance Imaging
Authors: Shveta Monga, Ladislav Valkovič, Damian Tyler, Craig A. Lygate, Oliver Rider, Saul G. Myerson, Stefan Neubauer, Masliza Mahmod
Journal: JACC. Cardiovascular imaging (2022)

Pressure overload in aortic stenosis (AS) encompasses both structural and metabolic remodeling and increases the risk of decompensation into heart failure. A major component of metabolic derangement in AS is abnormal cardiac substrate use, with down-regulation of fatty acid oxidation, increased reliance on glucose metabolism, and subsequent myocardial lipid accumulation. These changes are associated with energetic and functional cardiac impairment in AS and can be assessed with the use of cardiac magnetic resonance spectroscopy (MRS). Proton MRS allows the assessment of myocardial triglyceride content and creatine concentration. Phosphorous MRS allows noninvasive in vivo quantification of the phosphocreatine-to-adenosine triphosphate ratio, a measure of cardiac energy status that is reduced in patients with severe AS. This review summarizes the changes to cardiac substrate and high-energy phosphorous metabolism and how they affect cardiac function in AS. The authors focus on the role of MRS to assess these metabolic changes, and potentially guide future (cellular) metabolic therapy in AS.
Abstract 2772: A novel bio-physical based CDA approach for evaluating lung cancer therapeutic responses
Authors: Junjie Wu, Zixiu Zou, Xuedong Du, Yue Lin, Xing Tang, Jie Chen, Lan Peng, Chris Yu
Journal: Cancer Research (2022)

Abstract Background: Lung cancer is the world's highest mortality and incidence rate of malignancy, and the prognosis survival rate is significantly lower than other tumors. A novel bio-physics based multi (pan)-cancer test technology named Cancer Differentiation Analysis Technology (CDA) has been developed and investigated for evaluating and monitoring lung cancer therapeutic responses. Methods: A total of 686 patients diagnosed with different sub-types of lung cancer were included in this study. CDA levels were concurrently measured in peripheral blood obtained from 686 patients during the treatment. According to the response evaluation criteria in solid tumors (RECIST) 1.1 standard, the efficacy of 686 patients after treatment was evaluated, and the diagnostic efficacy of CDA technology was evaluated by receiver operating characteristic (ROC) curve. Results: Clinical pathological parameters of the patients are listed in Table 1. The higher the CDA value, the worse the curative effect. CDA value of lung cancer in CR (complete response) group was significantly lower than that in other 3 groups (p&amp;lt;0.05). CDA value of adenocarcinoma lung cancer in CR group were significantly lower than that in SD (stable disease) group (p&amp;lt;0.05). For non - metastatic lung cancer, CDA value in CR group was significantly lower than that in SD group (p&amp;lt;0.05) The receiver ROC analysis showed that the area under curve (AUC) of lung cancer group, NSCLC group, adenocarcinoma lung cancer group, were 0.756, 0.772, and 0.792, respectively. The AUC of early lung cancer group, and non - metastatic lung cancer group were 0.794, and 0.851. Conclusions: CDA appears to have the ability to predict and monitor therapeutic responses to lung cancer surgery and chemotherapy treatments. In most cases, the CDA of CR patients is low, and there is a good correlation between CDA and curative effect in early lung cancer. CDA could be a potential candidate for evaluating lung cancer, especially for early stage lung cancer therapeutic response. Citation Format: Junjie Wu, Zixiu Zou, Xuedong Du, Yue Lin, Xing Tang, Jie Chen, Lan Peng, Chris Yu. A novel bio-physical based CDA approach for evaluating lung cancer therapeutic responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2772.
Abstract 5978: Real time pathologic diagnosis of digital biopsy during lung cancer surgery using confocal laser endomicroscopy
Authors: Tae-Jung Kim, Young Jo Sa, Sung Ah Kim, Kyungmin Hwang
Journal: Cancer Research (2022)

Abstract Purpose: Portable hand held confocal laser endomicroscopy is a novel, noninvasive technology that provides real time imaging during biopsy procedure and could be used to perform rapid histopathological diagnosis. However, its ability of determining whether the ex vivo samples obtained during lung cancer surgery or biopsy are tumor or non tumor is yet to be evaluated. Methods: Real time imaging of 75 surgical samples was performed. In preanalytic process, the samples were stained with fluorescent dye. Benign and malignant histologic structures were classified by cell density, nuclear size variability, and nuclear arrangement, which are compared with HE images from the same section. Results: We defined the confocal laser endomicroscopy atypia classification from the findings of the cells and made a comprehensive atlas of digital biopsy images for pleural surface, bronchus, and lung parenchyma. A total of 3,734 digital images were correlated with 75 frozen lung specimens. Three pathologists assessed digital biopsy images for defining cancer versus non cancer. Overall accuracy was 92.2%, The sensitivity for malignancy was 100% and the specificity was 84.4%. Both inter observer (k = 0.51) and intra observer (k = 0.52) agreement confirmed moderate agreement. Conclusion: Portable confocal laser endomicroscopy was useful to differentiate malignant from benign, to assess the histology of pleural surface and bronchial margin and might be substitute for rapid on site evaluation of pathologic diagnosis during surgical or biopsy procedure. Citation Format: Tae-Jung Kim, Young Jo Sa, Sung Ah Kim, Kyungmin Hwang. Real time pathologic diagnosis of digital biopsy during lung cancer surgery using confocal laser endomicroscopy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5978.
Rising cost of living’s effect on infant feeding
Authors: Rosie McNee, Erin Williams
Journal: BMJ (2022)

<h3>Objective</h3> To decrease the incidence of bloodstream infection (BSI) for neonates &lt;29 weeks gestation through quality improvement. <h3>Design</h3> Commencing in September 2011, eight neonatal intensive care units (NICUs) in New South Wales and Australian Capital Territory, Australia participated in the Sepsis Prevention in NICUs Group project, a multicentre quality improvement initiative to reduce neonatal infection through implementation of potentially better practices and development of teaching resources. Data were collected for neonates &lt;29 weeks gestation from D3 to 35, using point of care data entry, for BSI, central line-associated BSI (CLABSI) and antibiotic use. Exponentially weighted moving average data trend lines for rates of BSI, CLABSI and antibiotic use for each NICU were automatically generated and composite charts were provided each month to participating NICUs. <h3>Results</h3> Between January 2012 and December 2014, data were collected from D3 to 35 for 1075 neonates &lt;29 weeks gestation who survived &gt;48 h, for a total of 33 933 bed days and 14 447 central line days. There was a significant decrease from 2012 to 2014 in BSI/1000 bed days (7.8±3.0 vs 3.8±1.1, p=0.000), CLABSI/1000 bed days (4.6±2.1 vs 2.1±0.8, p=0.003), CLABSI/1000 central line days (9.9±4.3 vs 5.4±1.7, p=0.012) and antibiotic days/100 bed days (31.1±4.3 vs 25.5±4.2, p=0.046). <h3>Conclusions</h3> This study demonstrates a &gt;50% reduction in BSI in extremely premature neonates from D3 to 35 following a collaborative quality improvement project to reduce neonatal infection across an NICU network, supported by timely provision of data.
Abstract 1567: Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer
Authors: Weikun Xiao, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, Reginald Hill
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with few effective treatments. Despite recent advances in in other cancers, the five-year survival rate of PDAC is still only 10%, with most patients succumbing to their disease within the first year. One of the main factors responsible for this poor outcome is the development of chemoresistance in nearly all clinical cases. While the intrinsic factors that facilitate chemoresistance in the tumor cells have been studied extensively, fewer studies have elucidated how the complex and unique microenvironment surrounding the tumor affects therapeutic responses. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there is a lack of high-throughput, easily tunable models to recapitulate this complex microenvironment, in order to identify a critical cell-extrinsic factors that could drive acquired chemoresistance in PDAC cells. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this system, we found that matrix-activated CAFs readily remodel the desmoplastic matrix through lysol-oxidase dependent crosslinking. Moreover, our novel system demonstrates how collagen-I and matrix stiffness affect chemoresistance via the hypersecretion CAF-derived exosomes. Interestingly, our data show that it is CAF-derived exosomes, not the organoid-derived exosomes, that are most important in regulation of proliferation and chemoresistance. Lastly, we identified key cell surface integrins for collagen-I as therapeutic targets to prevent desmoplastic matrix-mediated chemo-resistance in PDAC. Our study provides insights into how matrix composition and stiffness affect therapeutic outcome in PDAC. Moving forward, therapies aimed at interrupting how PDAC cells and stomal cells sense the matrix microenvironment could be utilized to eventually overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, Reginald Hill. Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1567.